Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. By using a system biology approach it has been discovered that KDM2B, a Jumonji-domain containing histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogates tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperates with KRASG12D to promote PDAC formation in mouse models in Jumonji-dependent manner. Gain and loss-of-function experiments coupled to genome-wide gene expression and chromatin immunoprecipitation studies revealed that KDM2B drives tumorigenicity by regulating developmental pathways and inducing metabolic reprogramming. Although PDAC is characterized by a well-defined number of genetic lesions, efforts to pharmacologically target those pathways have been unsuccessful. In contrast, the epigenetic networks involved in PDAC are poorly understood at the molecular level and explored as potential therapeutic targets. I generated new genetically engineered mouse models to conditionally ablate and overexpress KDM2B. I propose to conduct a forward genetic screen using the Sleeping Beauty transposon-mediated insertional mutagenesis system to identify oncogenic networks that cooperate with KDM2B in vivo to drive pancreatic cancer development. Given the reversibility of histone methylation and the importance of the Jumonji domain, I propose to use high throughput screening technologies to discover small molecule inhibitors of KDM2B and test their efficacy in vitro and in vivo. This proposal aims to provide further insights into the field of epigenetics of pancreatic cancer, facilitate the understanding of molecular mechanism(s) that drive oncogenesis through identification and testing new molecular targets in vivo, and provide a rich resource of potential cancer driving mutations for cross-comparative analyses with ongoing sequencing efforts in PDAC.